The cytokine, leukemia inhibitory factor (LIF), has been shown to be a potential therapeutic molecule for neurological disorders, including stroke. While LIF has been shown to activate cellular survival pathways, exact mechanisms have yet to be elucidated. Our laboratory has shown that LIF protects cultured oligodendrocytes (OLs) from oxygen glucose deprivation (OGD). One of its mechanisms is by increasing the expression of antioxidant enzymes, metallothinein-3 (Mt3) and peroxiredoxin-4 (Prdx4), to reduce extracellular oxidative stress. The proposed experiments will elucidate the LIF signaling mechanisms leading to the increased expression of the Mt3 and Prdx4 to reduce oxidative stress. Our hypothesis is that LIF protects oligodendrocytes exposed to ischemic conditions via antioxidant signaling. This proposal will utilize an in vitro model of ischemia to define the signaling pathway responsible for the protective and antioxidant effects of LIF. Moreover, we will expand on these results to determine in vivo whether delayed i.v. administration of LIF protects OLs in the rat brain from focal cerebral ischemia through increased antioxidant activity. Lastly we will test this delayed administration for its efficacy to enhance long-term behavioral recovery. This proposal will provide the data for additional animal studies to examine LIF as a potential therapeutic to widen the treatment window for stroke.